Transcript Testing a Mechanism: Kinetic Isotope Effects

Testing a Mechanism:
Kinetic Isotope Effects


Primary Isotope Effect - rate change due to
isotopic substitution at a site of bond breaking
or bond making in the rate determining step of
a mechanism.
Secondary Isotope Effect - rate change due to
isotopic substitution at other than a site of bond
breaking or bond making in the rate
determining step of a mechanism.
Primary Kinetic Isotope Effect:
Typical Values
Nuclide
klight
k heavy (at 25o C )
C-H/C-D
6-8
C-H/C-T
15 - 16
12
13
C/ C
12
14
16
14
C/ C
15
N/ N
18
O/ O
32
34
S/ S
35
37
Cl/ Cl
1.04
1.07
1.03
1.02
1.01
1.01
Examples of
Kinetic Isotope Effects
Consider the following dehydrohalogenation reactions:
CH3 CH2 CH2 Br
Case I:
CH3 CD2 CH2 Br
CH3
CH3 CH2 C Br
NaOC2 H5
H3 C
C2 H5 OH
H
NaOC2 H5
H3 C
C2 H5 OH
D
H2 O
H3 C
H
CH3
Case II:
CH3
CH3 CD2
C Br
C CH2
C CH2
C C
k / k = 6.7
H
D
o
1 KIE for C-H/C-D
CH3
CH3
k /k
H
H2 O
H3 C
D
CH3
C C
CH3
D
= 1.4
o
2 KIE for C-H/C-D
CH3
Rationale:
Transition State for Case I (E-2)

C2 H5 O
H
H (D)
H
C
C

(D)H
Br
H3 C
Transition State for Case II (E-1)
+ CH
CH3
3

H (D)
H (D)
CH3
CH3
C
C
+
rds
C
C

(D)H
(D)H
Br
BrH3 C
H3 C
More Examples of Kinetic
Isotope Effects
Consider the following decomposition of an azo compound:
R N
R N N R
Rationale:
N
R
2 R + N2
k14
N
k 15
N
= 1.02
Although the above rate enhancement is small in absolute terms,
for the nitrogen nuclides indicated, the enhancem ent is indicative
of a primary kinetic isotope effect.
Consider the nitration of benzene shown below:
C6 H6
C6 D6
Observation:
HNO 3 /H2 SO4
HNO 3 /H2 SO4
C6 H5 NO 2
rate
C6 D5 NO 2
rate D
H
rateH ~
= rateD
Conclusion to be drawn:
A C -H (C-D) bond is not being broken in the
rate determ ining step of electrophilic aromatic
nitration.
Secondary Kinetic Isotope
Effects
 Differences
in steric demand
 Hyperconjugative effects
 Differences in inductive effect
Examples of Secondary
Kinetic Isotope Effects
Differences in Steric demand
Example I:
CH3 Cl + H2 O
CH3 OH + HCl
kH
CD3 Cl + H2 O
CD3 OH + HCl
kD
Observation:
kH / kD = 0.97
H
Rationale:
H2 O
H
H
C
Cl
Example of an inverse
 -isotope effect
Example II:
In order to initiate bond making, the
incoming nucleophile m ust be able to
approach the substrate from the rear.
The shorter C-D bonds (relative to C-H
bonds) permit a closer approach byH2 O
and bond making can begin sooner.
(CH3 )2 CHOTs + H2 O
(CH3 )2 CHOH + TsOH
kH
(CH3 )2 CDOTs + H2 O
(CH3 )2 CDOH + TsOH
kD
Observation:
kH / kD = 1.13
H
C+
Rationale:
H3 C
CH3
In the transition state leading to the
isopropyl carbocation, there is a greater
relief of strain for C-H relative to C-D.
Secondary Kinetic
Isotope Effects
Exa mple I II:
+ CH3 I
N
N+
CH3
Observat ions:
Pyridine Subst ra te
k D / kH
CD3
1 .0 0 1
N
CD3
1 .0 0 9
N
1 .0 3 0
N
CD3
1 .0 9 5
D3 C
N
CD3
-
I
Secondary Kinetic Isotope
Effects
Hyperconjugative effects
Example:
 -Isotope effect
(CH3 )3 C Cl + H2 O
(CH3 )3 C OH + HCl
kH
(CD3 )3 C Cl + H2 O
(CD3 )3 C OH + HCl
kD
k
Observation:
H
/ k D = 1.21
+
CH3
Rationale:
H3 C
C+
CH3
CH2 H
H3 C
C
CH3
Whereas a C-D bond is slightly stronger than a C-H bond, hyperconjugation as
shown above is not quite as effective at stabilizing the carbocationic intermediate
for the reaction using deuterated reactant relative to that using unlabeled reactant.
Another view:
Whereas C-H bonds at a given tem perature are slightly longer than
corresponding C-D bonds, form ation of a carbocationic interm ediate
provides more relief from steric strain for unlabeled reactant
com pared with that experienced by deuterated reactant.
Secondary Kinetic Isotope
Effects
Inductive effects
Example:
CH3 COOH
+
CH3 COO + H
KH
CD3 COOH
+
CD3 COO + H
KD
KH / KD = 1.06
Observation:
Rationale:
Hydrogen is slightly more electronegative than deuterium.
Related Q uestion:
Which one of the following is more basic?
CH2 NH 2 vs.
CD2 NH 2